FGL1 Regulates Acquired Resistance to Gefitinib by Inhibiting Apoptosis in Non-small Cell Lung Cancer

Abstract

Background: This study investigated the role of fibrinogen-like protein 1 (FGL1) in regulating gefitinib resistance of PC9/GR non-small cell lung cancer (NSCLC). Methods: The effect of different concentrations of gefitinib on cell proliferation were evaluated using the CCK-8 assay. FGL1 expression in the normal human bronchial epithelial cell line Beas-2B, as well as four lung tumor cell lines, H1975, A549, PC9, and PC9/GR, was investigated by using western blotting and qRT-PCR. FGL1 was knocked down using small interfering RNA to evaluate the effects of FGL1 on PC9 and PC9/GR. The correlation between FGL1 expression and gefitinib resistance was determined in vitro via CCK-8 and colony formation assays, and flow cytometry and in vivo via flow cytometry and immunohistochemistry. Results: FGL1 expression was significantly upregulated in non-small cell lung cancer cells with EGFR mutation and higher in the gefitinib-resistant NSCLC cell line PC9/GR than in the gefitinib-sensitive NSCLC cell line PC9. Further, FGL1 expression in PC9 and PC9/GR cells increased in response to gefitinib treatment in a dose-dependent manner. Knockdown of FGL1 suppressed cell viability, reduced the gefitinib IC50 value, and enhanced apoptosis in PC9 and PC9/GR cells upon gefitinib treatment. Mouse xenograft experiments showed that FGL1 knockdown in PC9/GR tumor cells enhanced the inhibitory and apoptosis-inducing actions of gefitinib. The potential mechanism of gefitinib in inducing apoptosis of PC9/GR cells involves inhibition of PARP1 and caspase 3 expression via suppression of FGL1.Conclusions: FGL1 confers gefitinib resistance in the NSCLC cell line PC9/GR by regulating the PARP1/caspase 3 pathway. Hence, FGL1 is a potential therapeutic target to improve the treatment response of NSCLC patients with acquired resistance to gefitinib.

Whether cytidine deaminase of Mycoplasma hyorhinis promotes drug resistance by decomposing gefitinib

“…At present, the mechanism of EGFR-TKI resistance mainly focus on cell signaling pathways, such as OPN protein promoting EGFR-TKI resistance by activating downstream FAK/AKT and ERK signaling pathways to enhance αVβ3 expression [3], Cholesterol promotes the reexpression of ERR through EGFR/Src/Erk/SP1 signaling axis, thus leading to EGFR-TKI resistance [34]. FGL1 inhibits apoptosis of lung cancer cell by regulating PARP/caspase3 pathway [35].…”